
==== Front
Hepatol Commun
Hepatol Commun
HC9
Hepatology Communications
2471-254X
Lippincott Williams & Wilkins Hagerstown, MD

39298631
HEP4-24-0740
10.1097/HC9.0000000000000530
00004
3
Correspondence
Statins for the prevention of cirrhosis complications: An American emulation of the StatLiver Trial
Tapper Elliot B. etapper@umich.edu

Zhao Zhe zzhaozhe@med.umich.edu

Henderson James jbhender@med.umich.edu

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
Correspondence Elliot B. Tapper, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA. Email: etapper@umich.edu
10 2024
18 9 2024
8 10 e053014 7 2024
19 7 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

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pmcTo the editor,

Statins are hypothesized to prevent the progression of liver disease.1–6 StatLiver is a recently completed randomized trial from Europe that did not show an improvement in outcomes.7 This trial, however, closed early and missed its enrollment target.8 We conducted a trial emulation of StatLiver with the intention of examining a larger sample to evaluate the effect of atorvastatin in a nationally representative database of adult Americans with cirrhosis with Medicare insurance from 2008 to 2020. We used a new user design with a landmark of a new outpatient diagnosis of cirrhosis. All patients were followed from 90 days after cirrhosis diagnosis to the primary endpoint of StatLiver, which was death or transplantation. Liver-related hospitalizations were defined as hospitalization with decompensation: ascites (diagnosis code or paracentesis), spontaneous bacterial peritonitis, hepatorenal syndrome, TIPS, HE, or variceal bleeding. After applying StatLiver inclusion and exclusion criteria, we found 200 new users of atorvastatin and 52,345 nonusers, which were matched using inverse probability of treatment weighting using the variables shown in Table 1. Overall, 11.5% of the atrovastatin users and 14.0% of the nonusers were hospitalized (p = 0.31). Atorvastatin was associated with an incidence rate ratio for hospitalizations per person-year of 0.69, 95% CI (0.34–1.40). Decompensations occurred in 20% and 22% of patients, respectively (p = 0.89), with an subdistribution hazard ratio of 0.85, 95% CI (0.46–1.56) for atorvastatin. Death occurred in 13.5% of atorvastatin users and 12.5% of nonusers, with an subdistribution hazard ratio of 1.12, 95% CI (0.69–2.02) (Table 2). We conducted our study with a larger population of 400 subjects to maximize the data available for the intended 18 months. In contrast, StatLiver examined the outcomes of 78 subjects for a shortened 180 days. In StatLiver, 8% and 5% died in the atorvastatin and placebo arms within 180 days, respectively; 31.5% and 32.5% were hospitalized, respectively. In contrast, fewer patients in our study were hospitalized or died within 18 months. Although the StatLiver randomized patients with portal hypertension as determined invasively, we lacked such data. Although this is the greatest limitation of our emulation framework, portal pressures are not routinely measured in clinical practice. At the same time, the majority of enrollees in the StatLiver group had ascites, while 1 in 4 patients in our emulated study had ascites. However, the number of patients with ascites receiving atorvastatin in our emulation outnumbered the subjects in each arm of the StatLiver. Our trial emulation appears to confirm the findings of the StatLiver. Namely, atorvastatin did not improve the risk of hospitalization or decompensation in patients with cirrhosis. Our trial emulation extends the results of the StatLiver by providing data reflecting its intended duration and using a larger-than-expected sample size.

TABLE 1 Population

	Atorvastatin	No statins	p	
Demographics	
 n	200	200		
 Median age (SD)	67.5 (8.1)	66.5 (9.8)	0.24	
 Race	
  % White (n)	69.5 (139)	68.0 (136)	0.80	
  % Black (n)	18.0 (36)	20.5 (41)	0.80	
  % Other (n)	12.5 (25)	11.5 (23)	0.80	
% Male (n)	61.0 (122)	63.0 (126)	0.76	
% Urban (n)	62.0 (124)	60.5 (121)	0.83	
 Region	
  % Midwest (n)	14.5 (29)	13.0 (26)	0.82	
  % Northeast (n)	23.5 (47)	22.5 (45)	0.82	
  % South (n)	38.0 (76)	43.5 (87)	0.82	
  % West (n)	22.5 (45)	19.0 (38)	0.82	
  % Other (n)	1.5 (3)	2.0 (4)	0.82	
% Medicaid (n)	24.5% (49)	19.5 (39)	0.29	
Hepatic decompensations	
 % Ascites (n)	23.0 (46)	24.5 (49)	0.90	
 % HE (n)	13.0 (26)	14.0 (28)	0.89	
Etiology of liver disease	
 % Alcoholic (n)	18.0 (36)	19.5 (39)	0.94	
 % Viral/autoimmune/biliary (n)	30.0 (60)	29.5 (59)	0.94	
 % Neither (n)	52.0 (104)	51.0 (102)	0.94	
Medical history	
 % Fibrates (n)	10.5 (21)	11.5 (23)	0.87	
 % Insulin use (n)	29.5 (59)	30.5 (61)	0.91	
 % Hypertension medication (n)	63.0 (126)	66.5 (133)	0.53	
 % Hypertension diagnosis (n)	89.5 (179)	91.5 (183)	0.61	
 % Beta-blockers (n)	44.5 (89)	43.0 (86)	0.84	
 % Chronic heart failure (n)	47.0 (94)	45.5 (91)	0.85	
 % Myocardial infarction (n)	35.5 (71)	32.0 (64)	0.51	
 % Peripheral vascular disease (n)	39.0 (78)	43.0 (86)	0.48	
 % Cardiovascular disease (n)	34.5 (69)	37.5 (75)	0.61	
 % Hyperlipidemia (n)	71.0 (142)	71.5 (143)	1.00	
 % COPD (n)	46.0 (92)	43.5 (87)	0.70	
 % Chronic kidney disease (n)	18.5 (37)	20.5 (41)	0.71	
 % Diabetes (n)	23.0 (46)	24.0 (48)	0.90	
 % Gastroenterology consult (n)	33.5 (67)	32.0 (64)	0.83	

TABLE 2 Outcomes

Outcome	Atorvastatin (n = 200)	No statins (n = 200)	p	
Hospitalization	
 % (n)	11.5 (23)	14.0 (28)	0.31	
 Time to first hospitalization (IQR)	184 (71,342)	134 (48,225)		
 Hospitalization per person-year	0.24	0.27		
Death	
 % (n)	13.5 (27)	12.5 (25)	0.89	
 Time to event, d (IQR)	174 (72–299)	146 (74–357)		
Any decompensation	
 % (n)	20.0 (40)	22.0 (44)	0.90	
 Time to event, d (IQR)	168 (45–296)	139 (29–285)		
HE	
 % (n)	6.0 (12)	6.0 (12)	1.00	
 Time to event, d (IQR)	173 (56–361)	140 (36–289)		
Variceal bleeding	
 % (n)	2.0 (4)	1.5 (3)	1.00	
 Time to event, d (IQR)	150 (38–305)	133 (26–305)		
Ascites	
 % (n)	14.0 (28)	14.0 (28)	1.00	
 Time to event, d (IQR)	183 (45–309)	49 (18–152)		

AUTHOR CONTRIBUTIONS

Elliot B. Tapper is the guarantor of this article. Concept: Elliot B. Tapper. Analysis: Zhao Zhe, James Henderson, and Elliot B. Tapper. Data acquisition: Zhao Zhe, Elliot B. Tapper, and James Henderson. Writing: Elliot B. Tapper. Revision: Zhao Zhe and James Henderson.

FUNDING INFORMATION

Elliot B. Tapper received funding from the National Institutes of Health.

CONFLICTS OF INTEREST

Elliot B. Tapper has served as a consultant to Novartis, Axcella, and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has received unrestricted research grants from Gilead and Valeant. The remaining authors have no conflicts to report.
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